This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The insulin-degrading enzyme (IDE) is a 110 kDa zinc metallo-endoprotease that degrades many physiologically relevant substrates such as peptide hormones (insulin, insulin-like growth factor-II, glucagon, atrial natriuretic factor, and beta-endophin), amyloid &#946;peptide, and tumor growth factor-alpha. Functional studies have shown that IDE plays important roles in the regulation of developmental and metabolic processes as well as in the development of type 2 diabetes mellitus and Alzheimer?s disease. Thus, IDE is a promising therapeutic target for several human diseases. We have solved the structures of IDE alone and catalytically inactive IDE in complex with several biologically relevant substrates including insulin, amyloid &#946;, glucagon, and bradykinin. Our structures reveal how size, charge distribution, and the propensity of unfolding of IDE substrates could contribute their selective cleavages by IDE. We hypothesize that the list of IDE substrates is incomplete and our knowledge in the interaction of IDE with IDE substrates can be used to identify the novel substrates. Using this strategy, we have identified several novel IDE substrates and would propose to solve the structures of IDE with these substrates.